2-(aminoalkyl-amino)-4-amino thieno(3,2-d)pyrimidines

ABSTRACT

2-(AMINOALKYLAMINO)-THIENO(3,2-D)PYRIMIDINES OF THE FORMULA   2-(H2N-A-N(-R2)-),4-(R-N(-R1)-),R3-THIENO(3,2-D)PYRIMIDINE   WHEREIN R AND R1 MAY BE THE SAME OR DIFFERENT AND ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND STRAIGHT AND BRANCHED ALKYL OF 1 TO 6 CARBON ATOMS AND TAKEN TOGETHER WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED FORM A SATURATED 5 TO 7 MEMBER HETEROCYCLIC RING WHICH CAN OPTIONALLY CONTAIN AN OXYGEN OR NITROGEN HETEROATOM AND MAY BE SUBSTITUTED WITH ALKYL OF 1 TO 6 CARBON ATOMS OR HYDROXYL, R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND STRAIGHT AND BRANCHED ALKYL OF 1 TO 6 CARBON ATOMS, R3 IS SELECTED FROM THE GROUP CONSISTING OF METHYL IN THE 6- OR 7-POSITION AND HYDROGEN AND A IS A STRAIGHT OR BRANCHED ALKYLENE OF 2 TO 10 CARBON ATOMS AND THEIR NON-TOXIC, PHARMACEUTICALLLY ACCEPTABLE ACID ADDITION SALTS WHICH POSSES CARDIOVASCULAR AND SEDATIVE ACTIVITY AND INHIBIT PLATELET AGGREGATION, AND PROCESSES FOR THEIR PREPARATION.

United States Patent Office 3,838,121 2-(AMlNOALKYL-AlVIINO)-4-A1VIINOTHIENO [3,2-d]PYRlMID[NES Eberhard Woitun, Berthold Narr, and WolfgangSchroter, Biberach an der Riss, Germany, assignors to BoehringerIngelheim GmbH, Ingelheim am Rhein, Germany No Drawing. Filed Aug. 4,1970, Ser. No. 60,933 Claims priority, application Germany, Aug. 8,1969, P 19 40 572.2; July 2, 1970, P 20 32 686.7, P 20 32 687.8

Int. Cl. C07d 87/46 US. Cl. 260-2471 10 Claims ABSTRACT OF THEDISCLOSURE 2-(aminoalkylamino)-thieno [3,2-d1pyrimidines of the formulal Rs N N R/ R1 I wherein R and R may be the same or different and areselected from the group consisting of hydrogen and straight and branchedalkyl of 1 to 6 carbon atoms and taken together with the nitrogen atomto which they are attached form a saturated 5 to 7 member heterocyclicring which can optionally contain an oxygen or nitrogen heteroatom andmay be substituted with alkyl of 1 to 6 carbon atoms or hydroxyl, R isselected from the group consisting of hydrogen and straight and branchedalkyl of 1 to 6 carbon atoms, R is selected from the group consisting ofmethyl in the 6- or 7-position and hydrogen and A is a straight orbranched alkylene of 2 to 10 carbon atoms and their non-toxic,pharmaceutically acceptable acid addition salts which possesscardiovascular and sedative activity and inhibit platelet aggregation,and processes for their preparation.

OBJECTS OF THE INVENTION It is an object of the invention to provide thenovel thieno [3,2-d] pyrimidines of formula I and their addition salts.

It is a further object of the invention to provide novel processes forthe preparation of the compounds of formula I.

It is another object of the invention to provide novel therapeuticcompositions for inhibiting platelet aggregation.

It is an additional object of the invention to provide a novel method ofinhibiting platelet aggregation in Warmblooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

The novel Z-(aminoalkylamino)-thieno [3,2-d] pyrimidines of theinvention are selected from the group consisting of compounds of theformula wherein R and R may be the same or different and are selectedfrom the group consisting of hydrogen and straight and branched alkyl of1 to 6 carbon atoms and taken together with the nitrogen atom to whichthey are attached form a saturated 5 to 7 member heterocyclic ring whichcan optionally contain an oxygen or nitrogen heteroatom and may besubstituted with alkyl of 1 to 6 carbon atoms or hydroxyl, R is selectedfrom the group consisting of hydrogen and straight and branched alkyl of1 to 6 carbon atoms, R is selected from the group consisting of a methylin the 6- or 7-position and hydrogen and A is a straight or branchedalkylene of 2 to 10 carbon atoms and their non-toxic, pharmaceuticallyacceptable acid addition salts. Among the preferred compounds of formulaI are those where R and R together with the nitrogen atom to which theyare attached, form a morpholino ring optionally substituted With amethyl group.

The acid addition salts of the thieno [3,2-d] pyrimidines of formula Imay be derived from non-toxic, pharmaceutically acceptable inorganicacids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.,and organic acids such as succinic acid, tartaric acid, maleic acid,fumaric acid, etc.

The novel thieno [3,2-d] pyrimidines of formula I may be made by thefollowing methods.

METHOD A By reaction of a compound of the general formula t I! R3 s R1 RII wherein R, R and R have the above meanings and Z is a halogen atom, asubstituted mercapto group or an alkylsulfonyl group with a diamine ofthe formula R2 XHNAI1I-H II wherein R and A are as defined above and Xis a hydrogen atom or a protecting group easily split off, for example,acetyl, benzoyl or p-toluenesulfonyl group, and optionally splitting offthe protecting group X. If the radical Z is a halogen atom, the presenceof a hydrogen halide binding agent is required.

The reaction is performed at temperatures between 20 and 200 C.,preferably in the presence of an organic solvent. The hydrogen halidebinding agent may be an inorganic or tertiary organic base. There may,however, also be used at least a molar excess of the employed diamine ofgeneral formula III as acid binding agent. A further excess of thediamine may serve as the solvent. If X represents a protecting group,this is split off subsequently, for example by means of hydrolysis.

METHOD B By reaction of a compound of the formula wherein the radicals RR X and A have the above meanings and Z is a halogen atom, a free orsubstituted merwherein R and R are as defined above, and optionallysplitting off a protecting group X. If Z is a halogen atom, the presenceof a hydrogen halide binding agent is required for the reaction.

The reaction is performed at temperatures between and 200 C., preferablyin the presence of an organic solvent. The hydrogen halide binding agentmay be an inorganic or tertiary organic base. There may, however, alsobe used at least one molar excess of the employed amine as acid bindingagent. A further excess of this amine may serve as the solvent. If X isa protecting group, this is optionally subsequently split off, forexample by means of hydrolysis.

wherein the radicals R to R and A are defined as above and Z is ahalogen atom, with ammonia or with a carboxylic acid amide or acarboxylic acid imide or their metal salts and by subsequent splittingoff of the acid group from the originating carboxylic acid derivative.

The reaction is performed at temperatures between 20 and 200 C.,preferably in the presence of an organic solvent. When reacting withammonia, the reaction is preferably used with an excess of ammonia andthe reaction is carried out in a closed vessel. The carboxylic acidderivative formed when using a carboxylic acid amide or imide is splitwith acids or bases. Bases especially suitable are hydrazine andhydroxylamine.

METHOD D By catalytic reduction of a nitrile of the formula R, R VIIwherein the radicals R R R and R are defined as in the beginning and theradical A has the meaning of the radical A minus a methylene group,however.

The reduction is advantageously carried out with hydrogen activated inthe presence of Raney-nickel, palladium or platinum catalysts atelevated temperatures and elevated pressure. In general, temperaturesbetween and 100 C. at a pressure between 20 and 150 atmospheres aresufiicient.

METHOD E Compounds of formula I in which R, and R together with thenitrogen atom form a morpholino ring optionally substituted by an alkylgroup, are produced by intramolecular cyclization of a compound of theformula wherein the radicals X, R R and A are defined as above and R andR are hydrogen atoms or one of R or R is an alkyl of 1 to 6 carbon atomsand the other is a hydrogen atom in the presence of an acid condensationagent, and optionally splitting off a protecting group X.

The reaction is carried out in the presence of an acid condensationagent and optionally in a solvent at temperatures between 0 and C. Thecondensation agent may be acids such as sulfuric acid, phosphoric acid,perchloric acid, hydrochloric acid, hydrobromic acid, toluene sulfonicacid or anhydrous metal salts such as zinc chloride or a cationexchanger. The solvents may be higher hydrocarbons such as tetraline orthe acid used as condensation agent such as sulfuric acid or phosphoricacid. The reaction may, however, also be performed in the melt form.Moreover, it may be of advantage to perform the cyclisation under aninert atmosphere. The protecting group X is optionally split offsubsequently, for example by means of hydrolysis.

The preparation of the compounds of formula II used as startingmaterials is described in Germany Olfenlegungsschift No. 1,470,356,wherein a 3-amino-thiophene-2-carboxylic acid of the formula HzN ll HOOCor a reactive derivative thereof is reacted with urea or thiourea orcyanic or thiocyanic acid. The reactive derivatives of the3-aminothiophene-2-carboxylic acid proved to be especially suitable arethe esters and amides thereof. This forms compounds of the formulawherein R has the above meaning and B is a free hydroxy or mercaptogroup. If urea or cyanic acid is reacted with a compound of formula IX,there is formed a compound of formula X, wherein B is a free hydroxygroup. If thiourea or thiocyanic acid is used there is obtained acompound of formula X, in which B is the free mercapto group. Thesereactions are generally performed at elevated temperatures, preferablyat temperatures between 20 and 200 C. and optionally in the presence ofWater, When cyanic or thiocyanic acid is used, or in the presence of aninert, high-boiling solvent such as toluene, xylene ortetrahydronaphthalene.

The compounds of formula II, in which Z is a halogen atom, are producedby converting compounds of formula X, in which B is a free hydroxygroup, by conventional methods, for example by heating with a phosphorushalide, first into a compound of the general formula l lal in which Halis a halogen atom. These compounds are then reacted at room temperatureor at slightly elevated temperatures in a solvent, for example inethanol, with compounds of formula V. Thus, the starting compounds offormula II, wherein the radicals R R and R are defined as above and Z isa halogen atom, are formed.

For the production of compounds of formula II, in which Z is analkylmercapto or alkylsulfonyl group, compounds of formula X, in which Bis a free mercapto group, are converted by conventional methods, bytreating with alkylation agents, for example dialkylsulfates oralkylhalides, into the corresponding2-alkylmercapto-4-hydroxy-thieno[3,2-d]pyrimidines. These compounds areconverted by known methods, for example, by heating with a phosphorushalide, into compounds of the formula 2.1 XII wherein Alkyl is any alkylgroup and Hal is a halogen atom. These compounds are subsequentlyreacted at room temperature or at slightly elevated temperatures in asolvent, for example in ethanol, with compounds of formula V. Thus thestarting materials of formula II, wherein the radicals R R and R aredefined as above and Z is an alkylmercapto group, are formed. The thusobtained compounds of formula II may subsequently be converted, ifdesired, by means of oxidation agents, for example chlorine or potassiumpermanganate, into such compounds of formula 'II in which Z is analkylsulfonyl group.

Compounds of general formula III, wherein X is a protecting group, suchas for example, acetyl, benzoyl or p-toluenesulfonyl group, are producedaccording to methods known from the literature (see Houben/Weyl, vol.XI/l, page 26 ff).

The compounds of formula IV are produced, for example, by reaction of a3-amino-thiophene-2-carboxylic acid of formula IX or a reactivederivative thereof with thiourea or thiocyanic acid. The reactivederivatives of the 3- amino-thiophene-2-carboxylic acid proved to bespecially suitable are their esters and amides. Thereby are formed2-mercapto-4-oxy-thieno [3,2-d] pyrimidines in which the free mercaptogroup is subsequently alkylated by means of alkyl halides to obtain2-alkylmercapto-4-oxy-thieno [3,2-d] pyrimidines which are reacted withdiamines of formula III,

wherein R X and A are defined as above, to the corresponding2-aminoalkylamino-4-oxy-thieno [3,2-d] pyrimidines, after optionallysplitting off the radical X. These pyrimidines are subsequentlyhalogenated by means of phosphoroxyhalides to the starting materials offormula IV, in which Z is a halogen atom, or they are, for example,converted by means of diphosphorus-pentasulfide into the correspondingstarting compounds of formula IV having a mercapto group in 4-position.The thus obtained starting compound of formula IV may subsequently bealkylated, if desired, by means of alkyl halides by conventional methodsto form a compound of formula IV, in which Z is an alkylmercapto group.These compounds can easily be oxidized to compounds of formula IV, inwhich Z is an alkylsulfonyl group. The oxidation is preferably carriedout by means of chlorine or potassium permanganate.

The starting materials of formula VI are obtained by 6 reaction of2-hydroxyalkylamino-4-amino-thieno [3,2-d] pyrimidines of the formula R:N nan-1 1 f XIII wherein R is defined as above and A has the meaning ofA minus a methylene group, with compounds of formula II. Theaminonitriles of formula XIV are partially known from the literature ormay be produced by methods described in the literature (Houben/Wcyl,vol. XI/l, page 272 ff).

The starting materials of formula VIII may be produced from a2,4-dichloro-thieno [3,2-d] pyrimidine of formula XI by reaction with adiethanolamine and subsequently with an amine of general formula III. IfX represents a protecting group, this may subsequently be split offhydrolytically.

The novel compositions of the invention for inhibiting aggregation ofplatelets are comprised of a compound of formula I or its non-toxic,pharmaceutically acceptable acid addition salts and a major amount of apharmaceutical carrier. The compositions may be in the form of drinkableor injectable solutions or suspensions, tablets, coated tablets, drops,etc. The usual individual dose is 5 to mg., preferably 10 to 50 mg., ofthe active ingredient and the daily dose is 100 to 200 mg. per day ofthe active ingredient.

The method of the invention for inihibiting aggregation of platelets inwarm-blooded animals comprises administering to warm-blooded animals anamount of a compound of formula I or its non-toxic, pharmaceuticallyacceptable acid addition salts sufficient to inhibit aggregation ofplatelets. The said compounds may be administered transcutaneously ororally. The usual daily dose is 100 to 200 rug/kg.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments. Examples I to XIV show the preparation of thestarting materials and Examples 1 to 13 show the preparation of thefinal products.

EXAMPLE I 1.6 gm. (0.01 mole) of methyl 3-aminothiophene-2- carboxylateand 3 gm. (0.05 moles) of urea were admixed and then heated for 2 hoursat 200 C. to obtain a clear brown melt which solidified when cooled. Thesaid prod uct was dissolved in warm 2N aqueous sodium hydroxide and thesolution was decolorized with charcoal and made acidic with 2Nhydrochloric acid. The mixture was vacuum filtered to recover thecrystalline precipitate which was recrystallized from water to obtain1.2 gm. (72% yield) of 2,4-dioxythieno[3,2-d]pyrimidine melting at morethan 300 C.

Anaylsis.-C H N O S; molecular weight: 168.18. Calculated (percent): C,42.84; H, 2.40; N, 16.66. Found (percent): C, 42.75; H, 2.57; N, 16.82.

Using the same procedure, urea was reacted with methyl3-amino-S-methyl-thiophene-Z-carboxylate and methyl 3-amino-4-methyl-thiophene-Z-carboxylate to form2,4-dioxy-6-methyl-thieno[3,2-d] pyrimidine melting above 320 C., and2,4-dixy-7-methyl-thieno[3,2-d]pyrimidine melting above 300 C.,respectively.

EXAMPLE II A mixture of 8.4 gm. (0.05 mol) of 2,4-dioxy-thieno- [3,2-d]pyrimidine and 100 cc. of phosphorus oxychloride was refluxed for 10hours to obtain a clear solution and excess phosphorus oxychloride wasdistilled ofl in vacuo. The residual oil was added to a ice-watermixture and then the mixture was extracted with chloroform. Thechloroform extract was washed with water until the wash waters wereneutral, dried over sodium sulfate and distilled to dryness. The residuewas crystallized from ethanol to obtain 7.6 gm. (74% yield) of2,4-dichloro-thieno [3,2-d]pyrimidine melting at 141 to 142 C.

Analysis.-C H N O S molecular weight=299.38. Calculated (percent): C,35.13; H, 0.98; CI, 34.58. Found (percent): C, 35.25; H, 1.02; Cl,34.68.

Using the same procedure, phosphorus oxychloride was reacted with2,4-dioxy-6-methyl-thieno [3,2-d] pyrimidine and2,4-dioxy-7-methyl-thieno [3,2-d] pyrimidine to obtain2,4-dichloro-6-methyl-thieno [3,2-d] pyrimidine melting at 150 C. and2,4-dichloro-7-rnethyl-thieno [3,2d] pyrimidine melting at 186 C.respectively.

EXAMPLE III 5.1 gm. of (0.025 mol) of 2,4-dichloro-thieno [3,2-d]pyrimidine was added to 200 cc. of absolute ethanol and 4.8 gm. (0.055mol) of morpholine were added with stirring to the resulting suspensionwhile keeping the temperature at C. with cooling. The resulting clearsolution was allowed to stand for a short while during which acrystalline compound precipitated out and then the reaction mixture wasstirred for 2 hours. After vacuum filtration, the crystallineprecipitate was washed with water, then ethanol. The product wasrecrystallized from methyl ethyl ketone to obtain 5.75 gm. (90% yield)of 2-chloro-4-morpholino-thieno [3,2-d] pyrimidine melting at 196-198 C.

Analysis.C H ClN OS; molecular weight=255.74. Calculated (percent): C,46.97; H, 3.95; N, 16.44. Found (percent): C, 47.10; H, 4.03; N, 16.30.

Using the same procedure, the appropriate 2,4-dichloro-thieno [3,2-d]pyrimidine was reacted with the appropriate amino compound to obtain theproducts in 8 EXAMPLE IV A solution of 19.4 gm. (0.2 mol) of potassiumthiocyanate in 20 cc. of water were added dropwise with stirring over 30minutes to a solution of 15.7 gm. (0.1 mol) of methyl3-amino-thiophene-Z-carboxylate in cc. of hydrochloric acid warmed to 70C. and white crystals immediately began precipitating. The reactionmixture was heated for 2 /2 hours at 95 C. and the reaction mixture wasvacuum filtered. The crystalline precipitate was dissolved in 250 cc. of2N aqueous sodium hydroxide with heating. The cooled solution wasacidified with glacial acetic acid whereby an analytically pure compoundprecipitated out. After vacuum filtration, the crystals were washed withwater and dried to obtain 14.9 gm. (81% yield) of2-mercapto-4-oxy-thieno [3,2-d]pyrimidine melting above 300 C.

Analysis.C H N OS molecular weight=l84.25. Calculated (percent): C,39.12; H, 2.19. Found (percent): C, 39.20; H, 2.21.

EXAMPLE V A solution of 10.0 gm. (0.055 mol) of 2-mercapto-4-oxy-thieno[3,2-d1pyrimidine in 50 cc. of aqueous sodium hydroxidesolution was slowly added with stirring at 50 C. to 30.0 gm. of (0.275mol) of ethyl bromide and then the reaction mixture was refluxed for 2hours. After cooling, the clear solution was made acidic with glacialacetic acid and the mixture was vacuum filtered. The crystallineprecipitate was washed with Water and crystallized from ethanol toobtain 9.0 gm. (77% yield) of 2-ethylmercapt0-4-0Xy-thieno[3,2-d]pyrimidine melting at 201-203 C.

Analysis.-C H N OS molecular weight=212.30. Calculated (percent): C,45.26; H, 3.80; S, 30.21. Found (percent): C, 45.40; H, 3.85; S, 30.13.

EXAMPLE VI A mixture of 2.1 gm. (0.011 mol) of 2-ethylmercapto-4-oxy-thieno[3,2-d]pyrimidine and 60.0 gm. (1.0 mol) of1,2-diamino ethane was heated for 10 hours at C. in a sealed tube. Aftercooling the reaction mixture, the excess amine was distilled off invacuo. The residue was subjected to chromatography over a column of0.2-0.5 mm. silica gel with elution with a 7-3 mixture ofchloroform-methanol. The pure fractions were evaporated to dryness andthe residue was crystallized from a petroleum ether-ethanol mixture toobtain 0.59 gm. (28% yield) of 2 (Z-aminoethylamino) 4-oxy-thieno3,2-d]pyrimidine melting at 221 C. with decomposit1on.

Analysis.-C H N OS; molecular weight=210.27. Calculated (percent): C,45.69; H, 4.79; N, 26.64. Found (percent): C, 45.54; H, 4.86; N, 26.83.

EXAMPLE VII A mixture of 2.1 gm. (0.01 mol) of 2-(2-amino ethylamino) 4oxy-thieno[3,2-d]pyrimidine and 30 cc. of phosphorus oxychloride wasrefluxed for 2 hours and excess phosphorus oxychloride was distilled offin vacuo from the resulting clear solution. The residue was dissolved inwater and the aqueous solution was made alkaline with aqueous sodiumhydroxide solution with ice cooling. The aqueous phase was extractedwith methylene chloride and the organic extracts were washed with wateruntil the wash waters were neutral and then dried over sodium sulfateand distilled to dryness. The solid residue was crystallized fromethanol to obtain 0.48 gm. (21% yield) of 2-(2-aminoethylamino)-4-chloro-thieno [3,2-d]pyrimidine melting above 300 C.

Analysis.C H ClN S; molecular weight=228.72. Calculated (percent): C,42.01; H, 3.97; Cl, 15.50. Found (percent): C, 42.30; H, 4.06; CI,15.75.

9 EXAMPLE VIII A mixture of 5.1 gm. (0.02 mol) of2-chloro-4-morpholino-thieno[3,Z-dJpyrimidine and 15 cc. of amino l-'pentanol were heated at 120 C. for 4 hours and after cooling, the clearsolution was poured into water. An oil separated which crystallized uponstanding and then the reaction mixture was vacuum filtered. The crystalswere washed with water and crystallized from 70% methanol to obtain 3.6gm. (57% yield) of Z-(S-hydroxypentylamino) 4 morpholinothieno[3,2-d]pyrimidine melting at 118-119 C.

Analysis.-C H N O S; molecular weight=322.44. Calculated (percent): C,55.87; H, 6.88; N, 17.38. Found (percent): C, 55.79;H, 6.81; N, 17.50.

Using the same method, the appropriate thieno[3,2-d] pyrimidine andamino alcohol were reacted to obtain the compounds of Table II.

Ethanol-acetone zfitglpholino-thieno[3,2-d]pyrimidine- (2-1).

2-[(3-hydroxypropyl)ethylaminoH- 235 Do.

%rglpholino-thieno[3,2-d]pyrimid1ne- 2-[(e-hydroxybutyl)methylamino]-4-217 Do.

rfitrlpholino-thieno[3,2-d]pyrimidine- 2-[(4-hydroxybuty1)ethy1arnino1-4- 226-227 Do.

firglpholino-thienoBfl-d]pyrimidine- 2-[(4-hydroxybutyl)-n-proylarnlnoM- 160-163 Do.

1Hn g1pholino-thieno[3,2-d pyrimidine2-[(4-hydroxybutyl)-n-butylamino];4- 162-165 Do.

rfitgpholino-thieno[3,2-d1pyrnmdine- 2[(5-hydroxypentyl)ethylamino1-l-115-120 Ethanol.

:firglpholino-thieno[3,2-d]pyrim1dine-2-[(fi-hydroxyhexyl)methylamino]-4- 115 Do.

morpholino-thieno[3,2-d1pyrimidine- H Cl2-[(6-hydroxyhexy1)ethylamino]-4- Elientzpetroleummorpholino-thieno[3,2-d1pyrimidine. t herdetlgiyl acea e2-[(5-hydroxypentyl)butylamino]-4- 90 Isopropanol petroleum ether.

morpholino-thieno[3,2-d]pyrimidine- H01.

EXAMPLE IX 18 gm. (0.05 mol) of 2 (5 hydroxypentylamino)-4-morpholino-thieno[3,2-d] pyrimidine was added to 30 cc. ofthionylchloride and the mixture was allowed to stand overnight. Excessthionylchloride was distilled off in vacuo and the residue was added toa mixture of acetone or ether, The mixture was vacuum filtered and thecrystalline precipitate was dried to obtain 12.5 gm. (66.3% yield) of2-(5-chloropentylamino) 4 morpholino thieno[3,2d] pyrimidine-HCI meltingat 151-152 C.

Analysis.--C H Cl N O; molecular weight=377.29. Calculated (percent): C,47.80; H, 5.88; N, 14.87. Found (percent): C, 48.00; H, 6.01; N, 14.75.

Using the same procedure, thionyl chloride was reacted with theappropriate thieno[3,2-d]pyrimidine to obtain the products of Table III.

Illoorlpholino-thieno[3,2d]pyrim.idine-2-[(5ehloropentyl)-n-butylamino]-4- morpholino-thieno[3,2-d]pyrimidine.

Eluent: petroleum ether-ethyl acetate (1-1).2-[(G-chlorohexyl)methylaminol-4- Do.

morpholino-thieno[3,2-d1pyrimidine. 2-[(G-chlorchexyl)cthylamino]-4-morpholino-thieno[3,2-d1pyrimidine.

1 Oil, R; value=0.8.

EXAMPLE X 2.16 gm. (0.01 mol) of 2 methyl mercapto 4 chlorothieno[3,2-d]pyrimidine (produced from phosphorous oxychloride and 2 methylmercapto 4oxy-thieno- [3,2-d]pyrimidine melting at 71-73 C.) were added to 30 cc.of absolute ethanol and then 1.74 gm. (0.02 mol) of morpholine wereadded with stirringto the reaction mixture while cooling to 20 C. Thereaction mixture was then stirred for 3 hours at room temperature andwas then vacuum filtered. The precipitate was washed with water and thenethanol and crystallized from ethanol to obtain 2.05 gm. (77% yield) of2-methyl mercapto-4-morpholinothieno[3,2-d]pyrimidine melting at138-140" C.

Analysis.C H N OS molecular weight=267.38. Calculated (percent): C,49.44; CH, 4.90; N, 15.72. Found (percent): C, 49.21; CH, 4.95; N,15.84.

EXAMPLE XI A solution of 3.5 gm. (0.022 mol) of potassium permanganatein 25 cc. of water was added dropwise over 15 minutes to a solution of2.67 gm. (0.01 mol) of 2- methyl mercapto-4-morpholino-thieno[3,2d]pyrimidine in 25 cc. of glacial acetic acid and the reaction mixturewas then stirred for 2% hours at 25 C. The solution was decolored with asodium bisulfite solution and was then made alkaline by the addition ofaqueous sodium hydroxide solution. The aqueous phase was extractedseveral times with methylene chloride and the combined methylenechloride phases were washed with water, dried over sodium sulfate andevaporated to dryness in vacuo. The residue was crystallized fromethanol to obtain 1.84 gm. (62% yield) of2-methylsulfonyl-4-morpholinothieno[3,2-d]pyrimidine melting at 191193C.

Analysis.C H N O S molecular weight=299.38. Calculated (percent): C,44.12; H, 4.38; N, 14.03. Found (percent): C, 44.19; H, 4.45; N, 13.90.

EXAMPLE XII A mixture of 2.1 gm. (0.01 mol) of2-(2-aminoethylamino)-4-oxy-thieno[3,2-d] pyrimidine and 2.5 gm. (0.011mol) of phosphorus pentasulfide in 25 cc. of absolute pyridine wasrefluxed for 4 hours and the resulting clear solution was evaporated todryness in vacuo. The residue was added to 20 cc. of water and themixture was refluxed for 1 hour and then was cooled to 5 C. The pH ofthe solution was adjusted to 12 by the addition of 2N aqueous sodiumhydroxide and was then filtered through charcoal. Glacial acetic acidwas added to the solution which caused the formation of a precipitatewhich was recovered by vacuum filtration. The solid product was washedwith water and crystallized from dimethyl formamide to obtain 0.9 gm.(40% yield) of 2-(2-aminoethylamino)-4-mercapto-thieno[3,2-d]pyrimidinemelting at 249-250 C. (decomp).

AnaIysis.--C H N S molecular weight:226.23. Calculated (percent): C,42.46; H, 4.45; N, 24.76. Found (percent): C, 42.33; H, 4.47; N, 24.57.

EXAMPLE XIII 2.26 gm. (0.01 mol) of 2-(2-aminoethylamino)-4-mercapto-thieno[3,2-d]pyrimidine were dissolved in 40 cc. of 0.25Npotassium hydroxide solution and after cooling to C., 1.42 gm. (0.01mol) of methyl iodide were added thereto with stirring. An oil soonseparated and stirring was continued for 2 hours at 0 C. The mixture wasextracted several times with chloroform and the combined extracts werewashed with water, dried over sodium sulfate and evaporated to dryness.The residue was crystallized from ether to obtain 1.9 gm. (79% yield) of2-(2-aminoethylamino)-4-methyl mercaptothieno[3,2-d] pyrimidine meltingat 75 C. (decomp).

Analysis.C H N S molecular weight=240.36. Calculated (percent): C,44.96; H, 5.03; N, 23.31. Found (percent): C, 45.13; H, 5.10; N, 23.18.

EXAMPLE XIV A mixture of 5.2 gm. (0.02 mol) of2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 20 cc. of3-n-butylamino-propionitrile was heated at 150 C. for hours and thenexcess 3-n-butylamino-propionitrile was distilled off in vacuo. Theresidue was poured into water and the mixture was extracted severaltimes with methylene chloride. The methylene chloride extracts weredried over sodium sulfate and evaporated to dryness. The residue waspurified by chromatography over a silica gel column with elution with a2-1 mixture of petroleum ether and ethylacetate. The elution agent wasdistilled ofl? and the resulting yellow oil was dissolved in methanolichydrochloride and the addition of acetone caused the precipitation of5.0 gm. (65.4% yield) of 2-[(2-cyanoethyl)-n-butylamino]-4-morpholino-thieno 3 ,2-d] pyrimidine hydrochloride which melted at182-185 C. after crystallization from isopropanol.

Analysis.C H N ClOS; molecular weight=381.96. Calculated (percent): C,53.45; H, 6.33; N, 18.33; Cl, 9.27; S, 8.38. Found (percent): C, 53.50;H, 6.59; N, 18.45; Cl, 9.02; S, 8.33.

Using the same procedure, 2-chloro-4-morpholinothieno[3,2-d]pyrimidinewas reacted with 3-ethylaminopropionitrile and3-n1ethylamino-propionitrile to form 2-[(2-cyanoethyl)ethylamino]-4-morpholino thieno[3,2-d] pyrimidinehydrochloride melting at 180 C. and 2-[(2- cyanoethyl)methylamino] 4-morpholino-thieno[3,2-d] pyrimidine hydrochloride melting at 100101 C.,respectively.

EXAMPLE -I A mixtureof 5.2 gm. (0.02 mol) of2-chloro-4-m0rpholino-thieno[3,2-d]pyrimidine and cc. of1,2-diaminoethane was heated for minutes at 120 C. and after cooling,the reaction mixture was poured into a water-ice mixture. The aqueoussolution was made strongly alkaline by the addition of a 30% aqueoussodium hydroxide solution and was then extracted several times withmethylene chloride. The combined organic extracts were washed withwater, dried over sodium sulfate and evaporated to dryness. Thenon-crystalline residue was purified by chromatography over a silica gelcolumn with elution with acetone-methanol (7-3) mixture and the purefractions were evaporated to dryness. The noncrystalline residue wasdissolved in absolute ether and precipitation was eflected by additionof ethereal hydrochloric acid. The precipitate was recovered by vacuumfiltration, was washed with ether and was crystallized from absoluteethanol to obtain 4.5 gm. (64% yield of 2 (Z-aminoethylamino) 4morpholino-thieno[3,2-d]

12 pyrimidine dihydrochloride melting at 282-283" C. (decomp).

Analysis. C H N O S-2HC1 molecular weight: 352.30. Calculated (percent):C, 40.91; H, 5.44; N, 19.88; Cl, 20.13. Found (percent): C, 40.90; H,5.49; N, 19.79; Cl, 20.05.

Using the same process, the appropriate thieno[3,2-d] pyrimidine anddiamino alkane were reacted to form the products of Table IV.

TABLE IV Melting point Solvent of Product C.) crystallization2-(2-aminoethylamino)-6-methyl-4- 300-311 Methanol.

giggqholino-thieno[3,2-d]pyrimidine 2-[ (2-aniinoethyl)metl1ylan1ino1-4-275 Ethanol.

morpholino-tliieno[3,2-d1pyri1nidine- ZHOl.2-(2-aminopropylarnino)-4-morpholino- 1 214-216 Do.

thieno[3,2-d]pyrimidine-ZHCL 2-(2-amino-l-methyl propylarnino)-4- lIsopropanol.

norpholino-thieno[3,2-d]pyrimidine- 2-(3-aminopropylamino)-4-morpholino-255-258 Ethanol.

thieno[3,2-d1pyrimidine-2HC1. 2-(4-aminobutylamlno)-4-morpholino- 1245-247 Methanol-methylthieno[3,2-d]pyrimidine-2HC1. ethyl ketone (1-2).2-(6-aminohexylamino)-4-1norpholino- 1 280-282 Ethanol-acetonethieno[3,2-d]pyrimidine-2HO1. -1 2-(10-arninodecylamin0)4-1norpholino-184-186 Isopropanoltliieno[3,2-d1pyrimidine-2HC1. acetone (1-2).2-(3-aminopropylamino)-4-amino-thieno- 129-130 Ethanol.

[3,2-dIpyrimidine. 2-(2-aminoethylamino)-4-pentylamino- 1 273-275 Do.

thieno[3,2-d1pyrimidine-2HC1. 2-(4-aminobutylamino)-4-n-propylarnino-216-217 Ethanol-acetone thieno[3,2-d]pyrimidine-21101. (1-3).2-(2-arninoethylamino)-4-(2-n1ethyl- 276-278 Ethanol.

grllpgiholino)-thieno[3,2-d1pyrimidine-2-(2-aminoethylamino)-4-(4-methyl- 183-186 Methanol.

gg iazino)-thieno[3,2-d1pyrimidine- 2-(2arnin0etl1ylanuno)-4-(4-hydroxy-247-249 Ethanol.

piperidino-thieno[3,2-d]py1imicline- Ethanol-acetone Et(han)olacetone2-(4-aminobutylamino)-4-hexarnethylene- 123-125imino-thieno[3,2-d1pyrimidine-2HCl. 2-(2-aminoethylamin0)-4.-piperidino275-277 thieno[3,2-d1pyrimidine-2HC1.

1 Decomposes.

EXAMPLE II A mixture of 2.3 gm. (0.01 mol) of2-(2-aminoethylamino)-4-chloro-thieno[3,2,-d]pyrimidine and 15 cc. ofpyrrolidine was refluxed for 1 hour and the excess amine was distilledoff in vacuo. The residue was taken up in a 1N aqueous sodium hydroxidesolution and the solution was extracted several times with methylenechloride. The combined extracts were washed with water, dried oversodium sulfate and evaporated to dryness. The non-crystalline residuewas dissolved in absolute ether and the addition of etheral hydrochloricacid caused a precipitate to form which was recovered by vacuumfiltration. The solid was washed with ether and then was crystallizedfrom absolute methanol to obtain 1.2 gm. (36% yield) of 2- (2aminoethylamino) 4 pyrrolidino thieno[3,2 d] pyrimidine dihydrochloridemelting at 292-294 C.

Analysis. C H N S-2HCl; molecular weight 5 336.30. Calculated (percent):C, 42.85; H, 5.69; N, 20.83. Found (percent): C, 42.97; H, 5.76; N,20.85.

EXAMPLE III Step A A mixture of 16 gm. (0.0424 mol) of2-(5-chloropentylamino)-4-morpholino-thieno[3,2 d]pyrimidinehydrochloride and a solution of 17.5 gm. (0.094 mol) of potassiumphthalimide in 100 cc. of dimethylformamide were heated at 145 C. for 14hours and after cooling, the reaction mixture was added to water. Themixture was extracted with chloroform and the chloroform phase was driedover sodium sulfate and evaporated to dryness. The residue wastriturated with a mixture of ethyl acetatepetroleum ether and vacuumfiltered to obtain (52.3% yield) of 2-(S-phthalimido-pentylamino) 4morpholinothieno[3,2-d]pyrimidine melting at 122-124 C. aftercrystallization from a l-l mixture of ethyl acetate petroleum ether.

Step B A solution of 2.15 gm. (0.033 mol) of hydroxylamine hydrochloridein cc. of ethanol was added to 15 cc. of 4N methanolic sodium methylatesolution and the mixture was filtered to remove precipitated sodiumchloride. A solution of 3.82 gm. (0.00845 mol) of the phthalimidoderivative produced in Step A in 20 cc. of ethanol was added to thefiltrate and the reaction mixture was stirred for 2 hours at roomtemperature. The mixture was vacuum filtered to remove the gelatinousprecipitate of the sodium salt of N-hydroxyphthalimide and the filtratewas added to methanolic hydrochloric acid and then was evaporated todryness. The crystalline residue was crystallized from acetone-methanolmixture to obtain 1.94 gm (58.1% yield) of2-(S-aminopentylamino)-4-morpholino-thieno [3,2-d]pyrimidinedehydrochloride melting at 254- 256 C.

AItalysiS.-C H Cl N OS; 1110166111211 Calculated (percent): C, 45.70; H,6.40; N, 17.79; S, 8.12. Found (percent): C, 45.50; H, 6.56; N, 17.60;S, 8.24.

Using the same process, the appropriate4-morpholinothieno[3,2d]pyrimidine was reacted first with potassiumphthalimide and then with hydroxylamine to obtain the products in TableV.

morpholino-thieno[3,2-d1pyrimidine- 2H Cl.

Eluent: methanolgfiitliholino-thieno[3,2-d]pyrimidine]- ammonia (9-1).

1 Yellow oil, Rr value=0.5.

14 EXAMPLE 4 A mixture of 3.77 gm. (0.01 mol) of 2-(5-chloropentylamino)-4-morpholino-thieno 3,2-d] pyrimidine hydrochloride and 50 cc. ofliquid ammonia were heated at 100 C. in a sealed tube for 16 hours andafter cooling, excess ammonia was distilled oil and the residue waspurified by chromatography over silica gel with elution with a 6-1mixture of methanol-ammonia. The residue was taken up in a small amountof methanol and methanolic hydrochloric acid was added thereto followedby addition of acetone which resulted in the precipitation of 2-(5-aminopentylamino) 4-morpholino-thieno[3,2-d1pyrimidine dihydrochloridewhich after crystallization from a acetone-methanol mixture melted at254-256 C.

Using the same process, ammonia and 2-[(5-chloropentyl)methylamino]4-morpholino-thien0[3,2-d]pyrimidine hydrochloride was reacted to form 2[(S-aminopentyl)methylamino] 4-morpholino-thieno [3,2-d]pyrimidinedihydrochloride which after crystallization from a 1-2 mixture ofethanol-acetone melted at 255-257 C.

EXAMPLE 5 A mixture of 2.67 gm. (0.01 mol) of 2-methylmercapto4-morpholino-thieno[3,2-d]pyrimidine, 65 cc. of l,2-diaminoethane and 65cc. of glacial acetic acid was refluxed for 24 hours and then thereaction mixture was poured into Water and made alkaline with 30%aqueous sodium hydroxide. The aqueous phase was extracted with methylenechloride several times and the combined extracts were washed with waterand evaporated to dryness. The residue, which was a mixture of2-(2-aminoethylamino)-4-morpholino-thieno[3,2-d1pyrimidine and 2-(2-acetamidoethylamino) -4-morpholino-thieno [3 ,2-d] pyrimidine, was addedto 30 cc. of concentrated hydrochloric acid and the mixture was refluxedfor 8 hours and then cooled. The solution was made alkaline with 30%aqueous sodium hydroxide and was extracted with methylene chloride. Theorganic extracts were dried over sodium sulfate and evaporated todryness. The residue was dissolved in ether and etheral hydrochloricacid was added thereto. The resulting precipitate was recovered byvacuum filtration and was crystallized from ethanol to obtain 1.6 gm.(45% yield) of 2 (Z-aminoethylamino)4-morpholinothieno[3,2-d]pyrimidinedihydrochloride melting at 282- 283 C. (decomp.).

EXAMPLE 6 A mixture of 2.99 gm. (0.01 mol) of 2-methylsulfonyl-4-morpholino-thieno[3,2-d]pyrimidine and 25 cc. of 1,2- diaminoethanewas heated at C. for 30 minutes and the reaction solution wasconcentrated to /2 its volume in vacuo and was poured into a water-icemixture. The aqueous solution was made strongly alkaline by the additionof 30% aqueous sodium hydroxide and was then extracted several timeswith methylene chloride. The organic phase was washed with water, driedover sodium sulfate and evaporated to dryness. The residue was purifiedby chromatography and was then dissolved in absolute ether.Precipitation Was efiected by the addition of ethereal hydrochloric acidand the product was crystallized from absolute ethanol to obtain 2.9 gm.(82% yield) of 2 (Z-aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine dihydrochloride melting at 282-283 C. (decomp.).

EXAMPLE 7 A mixture of 2.4 gm. (0.01 mol) of 2-(2-aminoethylamino)4-methylmercapto-thieno[3,2-d]pyrimidine, 50 cc. of morpholine and 50cc. of glacial acetic acid was refluxed for 10 hours and was then pouredintowater. The aqueous solution was made alkaline with 30% aqueoussodium hydroxide solution and extracted several times with methylenechloride. The combined extracts were washed with water and evaporated todryness. The residue, a mixture of 2 (2aminoethylamino)-4-morpholinothieno[3,2-d]pyrimidine and2-(2-acetamidoethylamino)- 4 morpholino-thieno[3,2-d]pyrimidine, wasadded to 30 cc. of concentrated hydrochloric acid and the mixture wasrefluxed for 8 hours and then cooled. The mixture was made alkaline with30% aqueous sodium hydroxide solution and was then extracted withmethylene chloride. The methylene chloride extracts were dried oversodium sulfate and evaporated to dryness. The residue was dis solved inether and addition of etheral hydrochloric acid caused a precipitate toform. The precipitate has crystallized from ethanol to obtain 1.9 gm.(54% yield) of 2 (2 aminoethylamino) 4-morpholino-thieno[3,2-d]pyrimidine dihydrochloride melting at 282283 C. (decomp.).

EXAMPLE 8 A mixture of cc. of morpholine and 3.14 gm. (0.01 mol) of 2(2-acetylaminoethylamino)-4-methylsulfonylthieno[3,2-d1pyrimidine (madeby oxidation of 2-(2- acetamidoethylamino)4-methylmercapto-thieno[3,2-d] pyrimidine with potassium permanganate)melting 229 231 C. was heated at 75 C. for minutes and the solution wasevaporated to dryness in vacuo. The residue was added to 30 cc. ofconcentrated hydrochloric acid and the mixture was refluxed for 8 hoursand then was cooled. The mixture was made alkaline with 30% aqueoussodium hydroxide solution and was extracted with methylene chloride. Themethylene chloride was washed with Water, dried over sodium sulfate andevaporated to dryness. The residue was dissolved in ether and theaddition of etheral hydrochloric acid thereto caused a precipitate toform. Crystallization from ethanol gave 2.3 gm. (65% yield) of 2(2-aminoethylamino)-4-morpholinothieno[3,2-d]pyrimidine dihydrochloridemelting at 282- 283 C. (decomp.).

EXAMPLE 9 A mixture of 2.26 gm. (0.01 mol) of 2-(2-aminoethylamino)4-mercapto-thieno[3,2-d]pyrimidine and cc. of morpholine was refluxedfor 50 hours and excess amine was then distilled off in vacuo. Theresidue was purified by chromatography over silica gel and the free basewas treated with etheral hydrochloric acid followed by crystallizationfrom ethanol to form 0.4 gm. (11% yield) of 2- (2aminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine dihydrochloridemelting at 282283 C. (decomp.).

EXAMPLE 10 A mixture of 2.56 gm. (0.01 mol) of2-chloro-4-morpholino-thieno[3,2-d]pyrimidine and 4.08 gm. (0.04 mol) of1-acetylamino-2-aminoethane was heated at 120 C. for 2 hours and thencooled. The solution was poured into an ice water mixture and wasextracted several times with water. The organic phase was washed withwater, dried over sodium sulfate and evaporated to dryness. The residuewas crystallized from isopropanol to obtain 2.5 gm. (78% yield) of2-(2-acetylaminoethylamino)-4-morpholino-thieno[3,2-d]pyrimidine meltingat 174-176 C.

A mixture of 1.6 gm. (0.005 mol) of 2-(2-acetylaminoethylamino)-4morpholino-thieno[3,2-d]pyrimidine and 15 cc. of concentratedhydrochloric acid was refluxed for 8 hours and then was cooled. Thereaction mixture was poured onto ice and made strongly alkaline with a30% aqueous sodium hydroxide solution. The mixture was then extractedwith methylene chloride and the combined extracts were dried over sodiumsulfate and evaporated to dryness. The non-crystalline residue wasdissolved in abso lute ether and the addition of ethereal hydrochloricacid caused formation of a precipitate which was crystallized fromabsolute ethanol to obtain 0.7 gm. (40% yield) of 2-(2 aminoethylamino)4 morpholine-thieno[3,2-d] pyrimidine dihydrochloride melting at 282-283C. (decomp.).

1 6 EXAMPLE 11 10.7 gm. (0.035 mol) of2-[(2-cyanoethyl)methylamino]-4-morpholino-thieno[3,2-d]pyrimidine weredissolved in 200 cc. of methanolic ammonia and the mixture washydrogenated for 8 hours at room temperature with a hydrogen pressure ofatmospheres in an autoclave with 10 gm. of Raney nickel. The catalystwas filtered ofi? and the filtrate was evaporated to dryness. Theresidue was added to water and the pH of the resulting solution wasadjusted to 6 by the addition of dilute hydrochloric acid. The reactionmixture was extracted with chloroform, the aqueous phase was madealkaline and was extracted again with chloroform. The chloroform phasewas dried over sodium sulfate and evaporated to dryness. The residue wasdissolved in isopropanol and the addition resulted in the precipitationof 5.2 gm. (39.1% yield) of 2-[(3-aminopropyl methylamino-4-morpholino-thieno 3,2-d] pyrimidine dihydrochloride which aftercrystallization from ethanol melted at 245248 C.

By the same process, 2-[(2-cyanoethyl)ethylamino]-4-morpholino-thieno[3,2-d]pyrimidine and 2 [(Z-cyanoethyl)-n-butylamino]4-morpholino-thieno[3,2-]pyrimidine were hydrogenated using a Raneynickel catalyst to obtain 2-[(3-aminopropyl)ethylamino] 4morpholinothieno[3,2-d]pyrimidine dihydrochloride melting at 280 C. and2-[(3-aminopropyl)-n-butylamino]-4-morpholinothieno[3,2-d]pyrimidinedihydrochloride melting at 279- 281 C. after crystallization fromisopropanol.

EXAMPLE 12 A mixture of 2.56 gm. (0.01 mol) of2-chloro-4-morpholino-thieno[3,2-d] pyrimidine and 7.68 gm. (0.03 mol)of Z-(p-toluene sulfonamido)-ethyl ethylamine was heated for 6 hours atC. and after cooling, the light yellow solution was poured into water.The mixture was extracted with methylene chloride and the extracts weredried over sodium sulfate and evaporated to dryness. The residue waspurified by chromatography over silica gel with elution with a mixtureof benzene-acetone-methanol (60-25 15) and evaporation of the mixedsolvent to obtain 4.0 gm. (87% yield) of 2-[2-(p-toluenesulfonamido)ethyl ethylamino]-4-morpholino-thieno [3 ,2-d] pyrimidinemelting at 123-125 C. after crystallization from methanol. The free basewas reacted with methanolic hydrochloric acid to obtain thecorresponding hydrochloride salt melting at 249-251 C. aftercrystallization (from-methanol).

Analysis.C H C1N O S molecular weight=498.08. Calculated (percent): C,50.64; H, 5.67; N, 14.06; Cl, 7.12; S, 12.87. Found (percent): C, 50.85;H, 5.74; N, 13.95; Cl, 7.19; S, 12.60.

A mixture of 4.6 gm. (0.01 mol) of 2-[2-(p-toluene sulfon amido)ethylethylamino] 4 morpholino-thieno [3,2-d]pyrimidine and 50 cc. of a 40%solution of hydrobromic acid in glacial acetic acid and 1.8 gm. (0.02mol) of phenol were heated at 60 C. for 6 hours and then the solvent wasdistilled off under reduced pressure. The residue was added to water andthe solution was made strongly acidic with hydrochloric acid. Theaqueous phase was extracted with ethyl ether and then was made alkalinewhile cooling by the addition of potassium carbonate. The solution wasextracted with methylene chloride and the methylene chloride was driedover sodium sulfate and evaporated to dryness. The oily residue wasadded to methanolic hydrochloric acid to obtain 1.2 gm. (32% yield) of 2[(2-aminoethyl)-ethylamino]-4-morpholinothieno[3,2-d1pyrimidinedihydrochloride melting at 284- 285 C. after crystallization fromethanol.

Analysis.C H Cl N OS; molecular weight=380.27. Calculated (percent): N,18.45; C1, 18.65; S, 8.42. Found (percent): N, 18.25;.Cl, 18.40; ,S,8.23.

Using the same process, hydrobromic acid in glacial 1 7 acetic acid wasreacted with the appropriate thieno [3,2-d] pyrimidine to obtain theproducts of Table VI:

TABLE VII Melting point Solvent of TABLE VI Product C.) crystallizationMelting 2-[(3-aminopropyl)ethylamino1-4 280 Ethanol.

point Solvent of morpholin0-thieno{3,2-d]pyrimidine. Products C.)crystallization 2HC1.

2-[(5-aminopentyDethylaminol-4- 236-238 Ethyl acetate-2-[(2-annnoethyl)methylannno]-6-methyl- 293-295 Ethanol.m0rph0lino-thicno[3,2-d]pyrimidine. methanol (3-1).

4-morpholino-thieno[3,2-d]pyrimidine- 2H 2HCl.2[(G-aniinoheXyDmethyIaminoH- 227-228 Ethanol.2-[(Z-aminoethyl)n-propylamino1-4- 273 275 Methanol.morpholino-thieno[3,2-d]pyrimidine.

morpholino-thien0[3,2-d]pyrimid.ine- .ZHCl

2HC1. 2[(4-aminobutyl)n-butylamin01-4- 280 Ethanol-acetone.2-[(2-amin0ethyl)isopropy1amino1-4- 278-280 Ethanol.morpholino-thieno[3,2-d]pyrimidine.

morpholino-thien0[3,2-d]pyrimidine- 2HC1 ZHCl.2-[(2-aminoethyl)isopropylamino]-4- 278-230 Ethanol.2-[(2-aminoethyl)-n-butyl-amino]4- 271274 D0.morpholino-thieno[3,2-d1pyrimidine.

morpholino-thieno[3,2-d]pyrimidine- 2H 2HCl.2-[(2-arninoethylamino)-4-morpholino- 282-2832-[(3-aminopropyl)ethy1amino]-4- 280 Do. thieno[3,2-d] pyrimidine. 2HC1.

morpholino-thieno[3,2-d1pyrimidine- 2-(2-aminoethylamino)-6-methyl-4-309-311 Methanol.

2HC1. n1orpholino-thieno[3,2 d]pyrimidine.2-[(3-aminopropyl)-n-propy1amino1-4- 291-293 Do. 2HCl.

morpholino-thieno[3,2-d1pyrimidine- 2-[(2-aminoethyDmethylaminol-4- 275Ethanol.

2H 01. pholino-thieno[3,2-d] pyrimidine.

2-gii-aminggrgpylamiio)AgiEE ihoIinO- 214-216 Do.

2-[(3 benzamidopropyl)methylamino]-4-morpholino- 2-g-;$hgg}g sifiil$igggiholmov 255 258 D0. thlenowz'mpynmldme llydmlyzeq by refluxmfgWlth 2-( ifiriiilhdbiltfifiriEiQl-EihOrpholino- 245-247 Methanol-methylconcentrated hydrochloric acid to obtain a 34% yield ofthien0[3,2-d]pyrimidine.2HC1. ethzylketone 2-[(3aminopropyl)methylamino]-4-morpholino-thieno- 2 1 1 h 1280 282 t[3,2-d1pyrimidine dihydrochloride melting at 245248 C. 5 m0 Si ace oneafter crystallization from a 1-5 mixture of ethanol-ace- 255-257 z ggftone. 21101.

Analysis.C .;H Cl N OS; molecular weight=38 0.35. lDecomposes.

Calculated (percent): C, 44.20; H, 6.09; S, 8.43. Found (percent): C,43.95; H, 6.18; S, 8.14. E AMPLE 132.

Using the procedure of Example 13, 2-(2-aminoethyl- EXAMPLE 13amino)-4-[N-(2-hydroxyethyl) 2 hydroxypropylamino] A mixture of 237 gm(0.01 mol) of 4 th1eno[3,2-d]pyrim1dme d hydrochlor de was treated with6thanolamino 7 methyl thieno[3,2 d]pyrimidine prepared concentratedsulfuric acid to obtain 2-(2-amrnoethylfrom diethanolamine and2,4-dichloro-7-methyl-thieno- 219111102 4(Z'WethYImQTPhOImO)th1en?[3,2'd]PYnm1 [3,2-d]pyrimidine) and 10 cc. of1,2-diaminoethane were dme dlhydroPhlQnde meltmg at 276-278 P-) heatedat 120 C. for 4 hours and the excess amine was after crystalhzatlon fromethanoldistilled off in vacuo. The residue was purified by chro- 40EXAMPLE 13b matography over silica gel with elution with a 9-1 mixtureof methanol-concentrated ammonium hydroxide. The 2-[5 (p-t luenesulfonamido-pentyl)- th 1 i -4 P fractions were evaporated to y s a thediethanolamino-thieno[3,2-d]pyrimidine was treated with crystallineresidue was dissolved in excess ethanolic hydroconcentrated lf i id d hmsumng product was chloric acid and the SOh t H s evaporated to dryness-5 hydrolyzed with hydrobromic acid in glacial acetic acid T residue Wascrystallized from a mlXtuTe 0f l in the presence of a small amount ofphenol at 60 C. to 1101-efhfin01t0 Obtain y of obtain 2-[(S-aminopentyl)methylamino] 4 morpholinoethylamino)-4'dithan01amm0 7methyhthlenomid] thieno[3,2-d]pyrimidine dihydrochloride melting at 255-pyrimidine dihydrochloride melting at 235 (decomp.). 25 C.

Analysis.C H Cl N O S; molecular we1ght=384.34. 5O PHARMACOLOGICAL AM LS Calculated (percent): C, 40.62; H, 6.03; N, 18.22. Found (percent): C,40.45; H, 6.18; N, 18.11. Example A 3.8 gm. f of Tablets with 30 m g. of2-(2-aminoethylammo)-4-mor diethanolamino 7methyl-thieno[3,2-d]pyrim1d1ne dihya drochloride were dissolved in cc.of concentrated sulphohno thlenoml d1pynmldme dlhydrochlonde' furic acidand the mixture was allowed to stand for 3 days COMPOSITION at 20 C. 1nthtel absence oft moisture. tThe rlelgctizr 1 tablet contains M g. mmwas R Into a Wa emce 1 2 (2 aminoethylamino) 4 morpholino-thieno madealkaline with a 40% aqueous so iunr y roxi e so u- [sidlpyrimidinedihydrochloride 300 tron. The mixture was extracted several times withmeth- Lactose 38 0 ylene chloride and the combined extracts were washedwith u Potato starch 26.0 water, dried over sodium sulfate and then a dd to etheral polyvinylpyrrolidone hydrochloric acid. The resultingprecipitate of 2-(2-amino- Magnesium Stearate 1.0 ethylarnino) 7 methyl4 morpholin0-thien0[3,2-d] pyrimidine dihydrochloride was recovered byfiltration, 0 was washed with ether and crystallized from methanol toobtain 1.98 gm. (54% yield) of the said dihydrochloride COMPOUNDINGPROCEDURE melting at 335 C. (decornp). The active ingredient was mixedwith lactose and potato Analysis.C H Cl N OS; molecular weight=366.33-starch, moistened equally with a 20% ethanolic solution Calculated(percent): C, 42.70; H, 5.77; N, 19.10. Found of thepolyvinylpyrrolidone and granulated through a 1.5 (percent): C, 42.50;H, 5.88; N, 18.95. mm. mesh screen. The granulate was dried at 45 C. and

Using the same procedure, the appropriate 4-diethanolagain passedthrough a 1.0 mm. mesh screen and the thus amino thieno[3,2 d]pyrimidinedihydrochloride was obtained granulate was then mixed with magnesiumsteatreated with concentrated sulfuric acid to obtain the prod- H rateand pressed into flat 7 mm. tablets weighing nets of Table VII. mg.each.

1 9 Example B Coated tablets with mg. of 2-(4-aminobutylamino)-4-morpholino-thieno 3,2-d] pyrimidine dihydrochloride.

COMPOSITION 1 core of coated tablet contains Mg.

2 (4 aminobutylamino) 4 morpholino-thieno [3,2-d]pyrimidodihydrochloride 15.0 Lactose 14.0

Corn starch 8.0

Polyvinylpyrrolidone 2.5 Magnesium stearate 0.5

COMPOUNDING PROCEDURE The active ingredient was mixed with lactose andcorn starch, moistened equally with a ethanolic solution of thepolyvinylpyrrolidone and granulated through a screen of 1.5 mm. meshsize. The granulate was dried at 45 C. and again passed through a 1.0mm. mesh screen. The thus obtained granulate was mixed with magnesiumstearate and pressed into convex 5.0 mm. cores of coated tabletsweighing mg. The thus obtained cores were coated according to knownmethods with a shell consisting essentially of sugar and talcum. Thefinished coated tablets were polished by means of bees wax and weighed70.0 mg. each.

Example C Ampoules with 10 mg. of 2-(2-aminoethylamino)-4-Inorpholino-thieno [3 ,2-d pyrimidine-dihydrochloride.

COMPOSITION 1 ampoule contains Mg.

2-(2-aminoethylamino) 4 morpholino-thieno [3,2-d]pyrimidinedihydrochloride 10.0

Polyethylene glycol 600 100.0 Distilled water ad 2.0 cc.

COMPOUNDING PROCEDURE The polyethylene glycol and the active ingredientwere dissolved in boiled, distilled water cooled while introducingnitrogen. The solution was filled up to the indicated volume withdistilled water and filtered sterile. All work must be effected indiffuse light. The liquid was poured into brown 2 cc. ampoules whilenitrogen gasing and sterilized for 20 minutes at 120 C.

EXAMPLE D Drops with 10 mg. of2-(4-aminobutylamino)-4-morpholino-thieno- [3,2-d] pyrimidinedihydrochloride.

COMPOSITION 1 ml. of drop solution contains 2-(4-aminobutylamino) 4morpholino-thieno- [3,2-d]pyrimidine dihydrochloride mg 10.0 Cane sugarmg 350.0 Sorbic acid mg 1.0 Cocoa essence mg 50.0 Ethyl alcohol cc 0.2Polyethylene glycol 600 cc 0.1

Distilled water ad 1.0 cc.

COMPOUNDING PROCEDURE 20 PHARMACOLOGICAL STUDY Inhibition of PlateletAggregation The inhibition of platelet aggregation was determined bythree different methods. The first method was that of K. Breddin[Schweiz. Med. Wschr. Vol. 95, 655-660 (1965)] wherein human bloodplasma rich in platelets was, after the addition of the test compound,slowly rotated in a water bath. A siliconized glass holder wassubsequently covered with the rotated plasma, washed, fixed and colored.The inhibition of the aggregation of the platelets was determinedmicroscopically.

The second method for the determination of the inhibition ofplatelet-aggregation was that of Born et al. [J Physiol. Vol. 170, 397(1964)]. The aggregation was measured in the plasma rich in platelets ofhealthy test persons. The decrease of the optical density in thesuspension of platelets was measured and registered photometricallyafter addition of adenosin-diphosphate (10 mols per liter). The activesubstances were each added 10 minutes before the addition ofadenosin-diphosphate.

The third test for aggregation of platelets was that of Morris [1.Internationales Symposion uber Stoffwechsel und Membranpermeabilitat vonErythrozyten und Thrombozyten, Wien 1968, E. Deutsch, E. Gerlach, K.Moser; Georg Thieme-Verlag Stuttgart]. Human citrated blood was broughtinto contact for 30 seconds with 1 gm. of glass-balls. After the contactthe blood was allowed to stand for 1 hour to render possible thedesaggregation of the reversible aggregates. The platelets in the plasmawere counted microscopically before and after the contact withglass-balls.

According to these 3 test methods, the following substances showed agood inhibition of the aggregation of platelets still at a concentrationof 10* mols per liter:

2-[(S-aminopentyl)ethylamino]-4-morpholino-thieno- [3,2-d] pyrimidinedihydrochloride.

2-[ (S-aminopentyl)methylamino] -4-morpholino-thieno [3,2-d]pyrimidinedihydrochloride.

2-[ (3-aminopropyl)ethylamino] -4-morpholino-thieno- [3,2-d]pyrimidinedihydrochloride.

2- (Z-aminoethyl ethylamino] -4-morpholino-thieno- [3,2-d] pyrimidinedihydrochloride.

2-(2-aminoethylamino -4-morpholino-thicno [3,2-d]

pyrimidine dihydrochloride.

2-(3-aminopropylamino)-4-morpholino-thieno [3,2-d]

pyrimidine dihydrochloride.

2- (4-aminobutylamino -4-morpholino-thieno [3 ,2-d]

pyrimidine dihydrochloride.

2-[ 2-aminoethyl methylamino] -4-morpholino-thieno- [3,2-d] pyrimidinedihydrochloride and 2- (Z-aminopropyl amino -4-morpholino-thieno 3,2-d]

pyrimidine dihydrochloride.

Various modifications of the compositions and methods of the inventionmay be made without departing from the spirit or scope thereof and it isto be understood that the invention is to be limited only as defined inthe appended claims.

We claim:

1. A compound of the formula R2 N HZN.AI1I

l R: s it 371M wherein R is hydrogen or methyl, R is hydrogen, methyl orethyl, R is hydrogen, 6-methyl or 7-methyl, and

A is straight or branched alkyl of 2 to 6 carbon atoms, or a non-toxic,pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 which is selected from the group consisting of2-[(5-aminopentyl) ethylamino]-4- morpholino-thieno[3,2-d]pyrimidine andits non-toxic, pharmaceutically acceptable acid addition salts.

3. A compound of claim 1 which is selected from the group consisting of2-[(S-aminopentyl)-methylamino]-4- morpholino-thieno[3,2 dl-pyrimidineand its non-toxic, pharmaceutically acceptable acid addition salts.

4. A compound of claim 1 which is selected from the group consisting of2-[(3-aminopropyl)-ethylamino]-4- morpholino thieno[3,2-d]-pyrimidineand its non-toxic, pharmaceutically acceptable acid addition salts.

5. A compound of claim 1 which is selected from the group consisting of2-[(2-aminoethyl) ethylamino1-4- morpholino-thieno[3,2-d]-pyrimidine andits non-toxic, pharmaceutically acceptable acid addition salts.

6. A compound of claim 1 which is selected from the group consisting of2-(2-aminoethylamino)-4-morpholinothieno[3,2-d]pyrimidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.

7. A compound of claim 1 which is selected from the group consisting of2-(3-aminopropylamino) 4 morpholino-thieno[3,2-d1pyrimidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.

8. A compound of claim 1 which is selected from the group consisting of2-(4-aminobutylamino)-4-morpholinothieno[3,2-d]pyrimidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.

9. A compound of claim 1 which is selected from the group consisting of2-[(Z-aminoethyl)-methylamino]-4- morpholino thieno[3,2-d]-pyrimidineand its non-toxic, pharmaceutically acceptable acid addition salts.

10. A compound of claim 1 which is selected from the group consisting of2-(2-arninopropylamino)-4-morpholino-thieno[3,2-d]pyrimidine and itsnon-toxic, pharmaceutically acceptable acid addition salts.

References Cited Thomae, Chemical Abstracts, Vol. 67, p. 100149g (1967).

DONALD G. DAUS, Primary Examiner J. TOVAR, Assistant Examiner US. Cl.X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,838,121 Dated p 97 EBERI'TARD WQITUN BERTHOLD NARR and WOLFGANGSCHROTER Inventofls) It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

F001. 7, line 20 -.correct C H N O S i 1 to read --C6HgCl N S--;

- correct "299.38" to read --205.08--; A

line 60- correct "pyrimidone" to read "pyrimidine";

line 70- correct "[e,2-d1-" to read --(3,2 -d]-pyrimidine-.

" to read ---C8---.

C01. 8, line 3 L correct "C Col. 11, line 56 correct "5.2" to read--5.l2--;

line 7h insert closing parenthesis after "yield".

Col. 15, line 9 correct "has" to read --was--.

Col. 16, line 23 insert -c1- after "3,2".

Signed and sealed this 24th day of June 1975.

(SEAL) Attest:

C. "IARSHALL DANN RUTH C. MASON Commissioner of Patents AttestingOfficer and Trademarks

